Palmeiras advanced to the Copa Libertadores round of 16 and the Brazilian giants were joined by Group F rivals San Lorenzo.
Luiz Felipe Scolari's Palmeiras reached the knockout phase thanks to Thursday's 4-0 rout of Melgar, while San Lorenzo also progressed despite their 1-0 loss to Junior.
With one matchday remaining, Palmeiras have 12 points – two clear of second-placed San Lorenzo, who are six points ahead of Melgar.
Palmeiras were too good for Peruvian hosts Melgar in Arequipa, where attacker Gustavo Scarpa scored twice.
Gustavo Gomez – who is on loan from AC Milan – opened scoring with a powerful header in the 10th minute and Scarpa's powerful effort doubled the lead 12 minutes later.
Scarpa made it 3-0 in the 67th minute and substitute Moises completed the scoring with nine minutes remaining, while Melgar's Carlos Neyra was sent off for a second yellow card in stoppage time.
Colombia's Junior won their first match of the campaign after edging Argentinian visitors San Lorenzo 1-0.
Meanwhile, 10-man Cerro Porteno – already assured of a spot in the last 16 – went down 2-1 at Zamora, who snapped a 17-game losing streak, in Group E.